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The Best of Pill Pushing - Thalidomide - Every mother's nightmare - (7/25/2018)

Pill Pushing
The ways in which medications have changed our culture
Ron Gasbarro, PharmD
The drug in question: Thalidomide
Our culture at that time: In the carefree days of 1957 to 1962 – the post-World War II era, post-Eisenhower era, pre-Roe v. Wade and Beatles eras, and the blossoming moments of Camelot – there appeared an ominous cloud, delivered to us by the relatively new medium called television, which showed us the horrors of what a drug can do. Shocking images of children born with severe deformities filled TV screens. The cause was not immediately known. 
The good, the bad, and/or the ugly:  In 1957, a medication called thalidomide was developed in Germany as a sedative and as a cure for morning sickness during pregnancy. By 1960, it was sold over-the-counter throughout Europe and South America, in Canada, and in many other parts of the world, although it was never approved for sale in the US. Around that time, approximately 5,000 to 7,000 infants were born with the characteristics of phocomelia, an otherwise rare congenital disorder that produced limb foreshortening, as well as deformities of the ears, eyes, heart, alimentary canal and other anatomical structures [McBride, 1961]. Only 40% of these babies survived. Research also proved that although phocomelia was non-existent throughout the 40’s and 50’s, by the time the drug was released to the market in the late 50’s, cases of severe phocomelia soared. The direct cause was finally linked to thalidomide [Lee, 2011].
In the 1950s, the standard belief was that it was unlikely any drug could pass from the mother to the fetus in utero [Heaton, 1994]. Since then, researchers have discovered that birth defects result from not only thalidomide but also from its metabolites (remnants of a drug after it has been broken down in the body, usually by the liver). The metabolites of thalidomide can last up to 40 times longer in the body than thalidomide itself, continuing to disrupt normal embryonic development, leading to congenital defects [Lee, 2011]. 
Impact of the drug on our culture: Back in the early 1960s, the very mention of the word “thalidomide” was terrifying. Giving birth to a child with flipper-like limbs and a host of other medical problems was a challenge that few women wanted to experience. Thus, another word was thrust into the mainstream consciousness – abortion.  Given that the 14th amendment, which would secure a woman’s right to terminate a pregnancy, was at least a decade away, abortion was still illegal in the United States. Sherri Finkbine was the host of the televised children’s program Romper Room in Arizona – mother of 4 and pregnant with a fifth child – whose husband brought thalidomide home from Europe as a remedy for his wife’s morning sickness. Following the gruesome TV reports on how the drug affected babies, Finkbine made the difficult decision to terminate her pregnancy. Unable to secure a therapeutic abortion in the US because it was not yet legal, she attempted to have the procedure done in Japan but was denied a visa by the Japanese Consul. Finkbine was finally able to obtain an abortion in Sweden on August 18, 1962. It was confirmed at the time of the abortion that her child would have been severely malformed – no legs, one arm, and was so severely deformed that the fetus’ gender was indeterminate. The termination of Finkbine’s pregnancy is seen now as a pivotal event in the history of abortion rights in the United States [Planned, 2012]. Finkbine’s story helped change public opinion on abortion: 52% of respondents in a Gallup poll thought she had done the right thing. By 1965, most Americans - 77% - wanted abortion legalized when the health of the mother is in danger. Based on the Roe v. Wade case in 1973 in which another woman (Jane Roe) sued the District Attorney of Dallas County (Henry Wade) for her right to end her pregnancy, the Supreme Court of the United States made a landmark decision to deem abortion a fundamental right under the US Constitution.   
Roe v. Wade prompted a national debate that continues today about issues including whether, and to what extent, abortion should be legal, who should decide the legality of abortion, what methods the Supreme Court should use in constitutional adjudication, and what the role should be of religious and moral views in the political sphere. Roe v. Wade reshaped national politics, dividing much of the United States into pro-choice and pro-life camps while activating grassroots movements on both sides.
The tragedy led to stricter controls for drug development in the United States [Heaton, 1994]. The tragedy surrounding thalidomide and the FDA’s wise refusal to approve the drug helped motivate profound changes in the FDA. By passing the Kefauver-Harris Drug Amendments Act in 1962, legislators tightened restrictions surrounding the approval process for drugs to be sold in the US, requiring that manufacturers prove they are both safe and effective before they are marketed. Now, drug approval can take 8 to 12 years, involving animal testing and requiring tightly regulated human clinical trials.
Where the drug is today: A half-century after its withdrawal from the global market, thalidomide is currently undergoing a remarkable renaissance as a novel and powerful immunomodulatory agent, that is, the drug has the ability to alter or regulate one or more immune functions of the body. The agent is used to treat diseases like multiple myeloma (a cancer of a white blood cell normally responsible for producing antibodies),leprosy and cough associated with idiopathic pulmonary fibrosis (a chronic and ultimately fatal disease characterized by a progressive decline in lung function, caused by scarring of the lung tissue), and is being tested for cancers and autoimmune disorders, such as lupus [Horton, 2012; Detweiler-Short, 2010; Kumar, 2012; Beret, 2014]. Thalidomide still comes with warnings of birth defects and, when used to treat multiple myeloma, an increased risk of deep venous thrombosis (also known as DVT) and pulmonary embolus, or a clot in the lung [Thalomid, 2012]. The use of thalidomide to treat diseases today is still accompanied by a list of “don’ts.” [Thalomid, 2012] Females of reproducing age must avoid pregnancy for at least 4 weeks before beginning thalidomide therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must also commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with thalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of thalidomide therapy; two negative pregnancy tests must be obtained prior to initiating therapy. Thalidomide is present in the semen of male patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking thalidomide and for up to 28 days after discontinuing thalidomide, even if they have undergone a successful vasectomy. Male patients taking thalidomide must not donate sperm. Patients – female or male – must not donate blood during treatment with thalidomide and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus should not be exposed to thalidomide.
Ron Gasbarro, PharmD is a pharmacist, medical writer, and principal at Rx-Press.com. Read more at www.rx-press.com.
Detweiler-Short K, Hayman S, Gertz MA, et al. Long-term results of single-agent thalidomide as initial therapy for asymptomatic (smoldering or indolent) myeloma. Am J Hematol. 2010;85:737-40.
Heaton A [ed]. The Chemical Industry. London: Chapman & Hall; 1994; p. 40. 
Horton MR, Santopietro V, Mathew L, Horton et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med. 2012;157:398-406.
Kumar N, Sharma U, Singh C, Singh B. Thalidomide: chemistry, therapeutic potential and oxidative stress induced teratogenicity. Curr Top Med Chem. 2012; 12:1436-55.
Lee CJJ, Gonçalves LL, Wells PG. Embryopathic effects of thalidomide and its hydrolysis products in rabbit embryo culture: evidence for a prostaglandin H synthase (PHS)-dependent, reactive oxygen species (ROS)-mediated mechanism. FASEB J. 2011;25:2468-83.
McBride W. Thalidomide and congenital abnormalities. Lancet1961;ii:1358.
Planned Parenthood Advocates of Arizona. Sherri Finkbine’s abortion: Its meaning 50 years later. August 15, 2012. Available at: http://blog.advocatesaz.org/2012/08/15/sherri-finkbines-abortion-its-meaning-50-years-later/ 
Thalomid [prescribing information]. Summit, NJ: Celgene Corporation; 2013. 

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